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Diabetes ; 67(5): 923-935, 2018 05.
Article in English | MEDLINE | ID: mdl-29472249

ABSTRACT

Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.ß2m-/- mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8+ T-cell responses mediated by these human class I variants. NOD.ß2m-/--A2.1 mice were previously used to identify ß-cell autoantigens presented by this human class I variant to pathogenic CD8+ T cells and for testing therapies to attenuate such effectors. However, NOD.ß2m-/- mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-Kd and H2-Db classical class I variants either individually or in tandem (cMHCI-/-). Ablation of the H2-Ag7 class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II-/-). NOD-cMHCI-/- mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8+ T-cell development and T1D susceptibility to NOD-cMHCI-/- mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Disease Models, Animal , HLA-A2 Antigen/genetics , HLA-B Antigens/genetics , Mice , beta 2-Microglobulin/genetics , Animals , CRISPR-Cas Systems , Diabetes Mellitus, Type 1/therapy , Histocompatibility Antigens Class I/genetics , Humans , Mice, Inbred NOD , Mice, Knockout , Mice, Transgenic
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